CONICET | Buscador de Institutos y Recursos Humanos

Background Liver fibrosis results from repeated cycles of liver damage and scar formation. Little is known regarding the contribution of neural crest-derived cells (NCDCs) to the liver in health and disease. Although this tissue seems to be largely devoid of Peripheral Nervous System (PNS) cells, no in vivo mouse genetic lineage-tracing studies are reported so far. Objective: The aim of this work was to analyze the contribution of NCDCs and GLAST+ pericytes to the liver during fibrogenesis. Methodology: Wnt1Cre2;R26RTom and GLASTCreERT2;R26RTom mice were used. Two models of liver cirrhosis were applied: 1) chronic applications of thioacetamide (200mg/kg per dose; i.p.; 3 doses per week; survival: 1, 4 and 8 weeks), and 2) bile duct ligation (survival: 2 weeks). Contribution of NCDCs to liver was analyzed. Results: Wnt1Cre2;R26RTom animals showed a small number of NCDCs in the liver, corresponding to GFAP+ glia and hepatocyte-like cells (HLCs). GLASTCreERT2;R26RTom contributed to small numbers of desmin- pericytes as well as HLCs, but not to GFAP+ glia; Tom+ HLCs were only found when tamoxifen (Tx) was injected at postnatal day (P)-2 and not at P60. Fibrogenesis was found to induce a significant increase in the incidence of glia, HLCs in Wnt1Cre2;R26RTom mice. In these animals, desmin- GFAPweak myofibroblasts could eventually be found. Whereas, desmin- GFAPweak myofibroblasts and an increase in HLCs numbers were found in Tx P2 GLASTCreERT2;R26RTom animals. Contribution with myofibroblasts was also found in Tx P60 GLASTCreERT(2);R26RTom mice. No Tom+ HLCs were found in the liver of Tx P2 PLP1CreER;R26RTom mice with/without TAA treatment. Small numbers of GFAP- NCDCs, not in contact with peripheral axons, were found in bone marrow of adult Wnt1Cre;R26RTom mice. A 2 week-treatment with TAA was found to increase CD44+ GLAST+ Tom+ cell numbers in the peripheral blood of Wnt1Cre2;R26RTom mice and to decrease such stromal population within the bone marrow. Consistently, total and Tom+ CFU-F numbers were also reduced in the bone marrow of those animals. Conclusions: During normal development some HLCs seems to have an embryonic neural crest and/or an early postnatal GLAST+ pericyte origin. During liver fibrogenesis, the incidence of such subpopulation/s increases which might suggest a role in liver regeneration. Glia cells numbers increase with fibrogenesis. In addition, stromal NCDCs get likely mobilized from the bone marrow during this process. Finally, NCDCs and/or GLAST+ pericytes likely contribute with myofibroblasts in the fibrotic liver